This project is concerned with determining how pharmacologic agents modify membrane channels in heart to suppress arrhythmias. Most of our current understanding of the basis for antiarrhythmic drug action is based on cardiac action potential measurements or onvoltage clamp studies in nerve and skeletal muscle. Because of the complexity of the ionic currents in heart, it is difficult to obtain detailed information about membrane properties from voltage measurements alone. Also, it is not certain how closely ionic channels in nerve and skeletal muscle resemble those in heart. Under the present proposal, the membrane effects of antiarrhythmic agents will be evaluated directly in cardiac muscle using a more reliable voltage clamp method. The study is facilitated by the use of the rabbit Purkinje fiber, a cardiac preparation with relatively simple morphology. Preliminary investigations have shown this preparation to be superior for voltage clamp study, since the fast sodium current and the slow plateau currents can be recorded without the complications of nonuniformity in membrane potential and ion concentration attending other cardiac voltage clamp experiments. Experiments will be performed with a spectrum of antiarrhythmic agents, including quinidine, procaine amide, lidocaine and diphenylhydantoin. I also propose to extend the investigation to both normal tissue and fibers which have been depressed by hypoxia, or by changes in the external pH or potassium ion concentration. If successful, the project should contribute substantially to the understanding of the mechanism of antiarrhythmic drug action in heart muscle.